PANCREATIC HORMONES

L.A. Olayaki
Anatomy of the pancreas:
Both an exocrine and endocrine organ
Cells with exocrine function release an
alkaline fluid containing sodium
bicarbonate and enzymes →
pancreatic duct → small intestine
Pancreatic “juice” aids in breakdown and
digestion of food in the small intestine
Pancreatic exocrine cells = acinar cells

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Endocrine Function :
Cells of the Islet of Langerhans synthesize and
release hormones into the circulation.
Hormones travel through the bloodstream to
target tissues (especially liver and muscle)
At the target cells, hormones bind specific
receptors and cause cell changes that control
metabolism

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 Pancreatic endocrine cells regulate carbohydrate,
fat, protein metabolism
• The islets are endocrine tissue containing 4 types
of cells.
• In order of abundance, they are the:
• b cells-secrete insulin and amylin;
• a cells- secrete glucagon;
• d cells-secrete somatostatin and gastrin
•  cells-secrete a polypeptide of unknown function.
(36 aa and plays a role in food intake)
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Insulin Synthesis and Secretion
Structure of Insulin
Insulin is a protein, with a molecular weight of about
6000 Daltons.
composed of 2 chains held together by disulfide bonds.
The figure shows a molecular model of bovine insulin,
with the A chain colored blue and the larger B chain
green.
The amino acid sequence is highly
conserved among vertebrates, and
insulin from one mammal almost
certainly is biologically active in
another. For years diabetic patients
were treated with insulin extracted
from pig or cow pancreases.
Biosynthesis of Insulin
Insulin is synthesized in significant quantities only in b cells
in the pancreas.
The insulin mRNA is translated as a single chain precursor
called preproinsulin, and removal of its signal peptide
during insertion into the endoplasmic reticulum
generates proinsulin.
Proinsulin consists of three domains: an amino-terminal B
chain, a carboxy-terminal A chain and a connecting
peptide in the middle known as the C peptide.
Within the endoplasmic reticulum, proinsulin is exposed to
several specific endopeptidases which excise the C
peptide, thereby generating the mature form of insulin.
Insulin and free C peptide are packaged in the Golgi into
secretory granules which accumulate in the cytoplasm.
Since insulin was
discovered in 1921, it
has become one of the
most thoroughly
studied
molecules in scientific
history.
 EFFECTS OF INSULIN
• CHO metabolism-promotes liver and muscle uptake
of glucose by stimulating phosphorylation and
inhibits gluconeogenesis
• Fat metabolism-promotes fat synthesis and storage
• Protein metabolism- promotes protein synthesis
and storage
• Growth- along with GH, promotes growth
• Increased transport of K+ and phosphate into cells
 CONTROL OF INSULIN SECRETION
• Stimulated by-bld glucose, bld free fatty
acids, bld amino acids, GIT hormones
(gastrin, CCk, GIP), glucagon, parasympathetic
stimulation, insulin resistance, obesity,
sulfonylurea drugs
• Inhibited by:  bld glucose, fasting,
somatostatin, catecholamines
PATHOPHYSIOLOGY OF INSULIN SECRETION
• Hyposecretion
• Diabetes mellitus comprises a heterogeneous group
of disorders characterized by high blood glucose
levels.
• Four major types of diabetes have been defined by
the World Health Organization (WHO):
• Type 1-Insulin-dependent diabetes mellitus (IDDM),
5-10%
• Type 2-Non-insulin-dependent diabetes mellitus
(NIDDM), 90-95%
• Gestational diabetes mellitus (GDM), and
• Diabetes secondary to other conditions.
 DIAGNOSIS
• Diabetes can be diagnosed by the presence
of the classic signs and symptoms of
diabetes (polyuria, polydipsia and
polyphagia) and unequivocally elevated
blood glucose levels,
• By fasting plasma glucose (FPG) ≥ 140 mg/dl,
or
• By venous plasma glucose ≥200 mg/dl at 2
hours after a 75-g oral glucose challenge.
 Type 1 Diabetes Mellitus
• Type 1 diabetes is a chronic inflammatory disease
caused by a selective destruction of insulin-
producing β-cells of the islets of Langerhans
• Onset predominantly in youth but can occur at any
age
 CHARACTERISTICS OF TYPE 1 DM
• Increased bld glucose, 300-1200mg/dl
• Loss of glucose in urine
• Dehydration, due to cell dehydration as a result of
high plasma osmolality and osmotic diuresis
• Tissue injury-bld vessels and neurons
• Increased utilisation of fats metabolic acidosis
due to acetoacetic, ß-hydroxybutyric acid and
acetone
• Depletion of body proteins-proteins used in place of
glucose  wt loss.
 Factors Influencing the Development of
Islet Autoimmunity
• Genetic Factors- first-degree type 1 diabetes family
history
• Environmental Factors- include dietary factors and
common viral infections
• Dietary Factors- short duration of breast-feeding,
the uptake of cow’s milk proteins during the 1st
months of life, and the early introduction of cereals
• Viral Infections- Viruses may induce islet
autoimmunity molecular mimicry between amino
acid sequences of viral peptides and islet antigens
that can activate autoreactive T-cells
 Factors Influencing the Development of
Islet Autoimmunity
• Maternal Transfer of Islet Autoantibodies-The
influence of maternally transmitted islet
autoantibodies (IAAs) on the development of islet
autoimmunity and type 1 diabetes has been
examined in both animal models and humans.
• Induction of Experimental Type 1 Diabetes
Mellitus in Animals- Using Alloxan, Streptozotocin,
Anti-insulin serum, Pancreatectomy, Dithizone,
• Genetic Models of Diabetic Rats- Animal Models
that Spontaneously Develop Diabetes, Genetically
Engineered Diabetic Mice
 Type 2 Diabetes mellitus
• This is the most common form of diabetes.
• Constitutes about 90% of total cases of diabetes.
• Closely linked to obesity.
• About 90% of type 2 diabetes is attributable to
excess weight.
• It is known that by the time hyperglycaemia
develops, reductions in both insulin sensitivity and
beta cell function have already altered
• Onset predominantly after age 40 years but can
occur at any age
 Factors Influencing the Development
Type 2 DM
• Genetics-a number of different genes may
contribute, some of which may be obesity genes.
• Age and Aging-Aging is typically associated with
diminished insulin sensitivity
• Dietary Constituents-Diets that contain increased
fat tend to promote a reduction in insulin
sensitivity, while consumption of increased amounts
of carbohydrate is associated with an increase in
insulin sensitivity.
• Exercise- Exercise has both acute and chronic
effects on insulin sensitivity
 Factors Influencing the Development
Type 2 DM
• Obesity-Central body fat accumulation is associated
with insulin resistance whereas peripheral body fat
accumulation seems to be of less critical
importance
• Drugs-A number of medications including
corticosteroids, growth hormone, and nicotinic acid
have all been shown to induce insulin resistance.
• Induction of Experimental Type 2 Diabetes
Mellitus in Animals-Fructose, High fat diet,
streptozotocin
 Gestational Diabetes (GDM)
• Glucose intolerance that has its onset or recognition
during pregnancy
• Associated with older age, obesity, family history of
diabetes
• Conveys increased risk for the woman for
subsequent progression to NIDDM
• Associated wlth increased risk of macrosomia
 Other specific types of DM
• Genetic defects of β-cell function-Chromosome 12-
HNF-1α (MODY3), chromosome 7-glucokinase
(MODY2), chromosome 20-HNF-4 α (MODY1),
chromosome 13-insulin promoter factor-1 (IPF-1;
MODY4), chromosome 17-HNF-1 β (MODY5),
chromosome 2-NeuroD1 (MODY6), mitochondrial DNA
and others.
• Genetic defects in insulin action-Leprechaunism,
Rabson-Mendenhall sydrome, Lipoatrophic diabetes
and others.
• Diseases of the exocrine pancreas-Pancreatitis,
trauma/pancreatectomy, neoplasia, cystic fibrosis,
haemochromatosis, fibrocalculous pancreatopathy and
others.
 Other specific types of DM
• Endocrinopathies-Acromegaly, Cushing’s syndrome,
glucagonoma, pheochromocytoma, hyperthyroidism,
somatostatinoma, aldosteronoma and others.
• Drug- or chemical-induced-Vacor, pentamidine,
nicotinic acid, glucocorticoids, thyroid hormone,
diazoxide, β-adrenergic agonists, thiazides, dilantin, α-
interferon and others.
• Infections- Congenital rubella, cytomegalovirus and
others
• Other genetic syndromes sometimes associated with
diabetes- Down’s syndrome, Klinefelter’s syndrome,
Turner’s syndrome, Wolfram’s syndrome, Friedreich’s
ataxia, , Huntington’s chorea, Laurence-Moon-Biedl
syndrome, myotonic dystrophy, porphyria, Prader-Willi
syndrome and others.
 DIAGNOSIS
• Diabetes can be diagnosed by the presence
of the classic signs and symptoms of
diabetes (polyuria, polydipsia and
polyphagia) and unequivocally elevated
blood glucose levels,
• By fasting plasma glucose (FPG) ≥ 140 mg/dl,
or
• By venous plasma glucose ≥200 mg/dl at 2
hours after a 75-g oral glucose challenge.
 PHYSIOLOGY OF DIAGNOSIS OF DM
• Presence of glucose in the urine
• Fasting Blood Glucose (Normal is 70-110mg/dl)- above is abnormal
• Glucose Tolerance test
75g of oral glucose
Followed by plasma
glu at 1, 2, and 3hr.

• Plasma Insulin-Type 1, low or undetectable; Type 2-high

• Acetone Breath-Present in Type 1, but not in type 2
 COMPLICATIONS OF DM
• Macroangiopathy-due to artherosclerosiscoronary
artery dx, stroke, peripheral vascular dx
• Microangiopathy due to basement membrane
thickening retinopathy, nephropathy and neuropathy
• Retinopathy-due to microaneurysm and exudates
blindness
• Nephropathy  renal failure
• Neuropathy  autonomic dysfunction, impotence, foot
ulcer etc
• Others- poor wound healing, cataract, bone and joint
dx, skin dx etc
 TREATMENT OF DM
• Diet- energy intake to achieve and maintain
desirable weight.
• Lifestyle- exercise, stop smoking and alcohol
• Oral Hypoglycaemic Agents-Sulfonylureas (stimulate
insulin release), Biguanides (reduce
gluconeogenesis),
• Insulin- for Type 1.
 HYPERINSULINISM
• Rare
• Due to adenoma of islet of Langerhans
• Results into low Glucose level
• Effects more on CNS, bcs depends only on
glucose
• Can results into coma
Treatment
• Intravenous glucose
• Glucagon and Epinephrine- To stimulate
gluconeogenesis in the liver
 GLUCAGON
• Secreted by α-cells of the islet of
Langerhans when bld glucose cocn falls
• It inceases bld glucose
• A polypeptide, mol. Wt. 3485, 29aa chain
Effects on glucose metabolism
• Causes glycogenolysis
• Increases gluconeogenesis
 OTHER EFFECTS OF GLUCAGON
• Inhibits fat storage
• Enhances strength of heart muscle
• Increases bld flow in some tissues-kidney
• Enhances bile secretion
• Inhibits gastric acid secretion
REGULATION
• Inhibition-Increased bld glucose
• Stimulation-Increased bld amino acids, Exercise
 SOMATOSTATIN
• Secreted by -cells of the islet of Langerhans
• Polypeptide, 14aa
• FUNCTIONS
• Inhibits secretion of insulin and glucagon
• Decreases motility of stomach, duodenum and gall
bladder
• Decreases secretion and absorption in the GIT
Secretion stimulated by:
•  bld glucose, amino acids, fatty acids,  cocn of
GIT hormones
 PANCREATIC POLYPEPTIDE
• Produced by  (PP) cells of isletof Langerhans
• Regulate endocrine and exocrine secretion of
the pancreas
• Reduced food intake in rodents
• Secretion increased by protein meal, fasting,
exercise and acute hypoglycaemia
• Secretion reduced by somatostatin and IV glu
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REGULATION OF BLOOD GLUCOSE
Fasting bld glucose is normally maintained btw 80-
90mg/dl, and about 120-140mg/dl 1-2hrs after a
meal.
• Mechanisms of achieving this:
• Liver function as bld glucose buffer
• Insulin and glucagon function as feedback control
systems
• In severe hypoglycaemia, hypothalamus
sympathetic nervous system NS to secrete
epinephrine liver to release glucose
• In prolonged hypoglycaemia (hrs & days), GH
&Cortisol glu utilisation but fat utilisation
 REGULATION OF BLOOD GLUCOSE
• Bld glucose regulation is omportant bcs brain, retina
& germinal epithelium of gonads only use glucose
as source of energy
• Too high bld glucose result into:
• Cellular dehydration due to osmotic effect
• Loss of glucode in the urine
• Osmotic diuresis depletion of body electrolytes
and water
• Damage to tissues heart attack, stroke, renal dx
and blindness